Br J Cancer 17" (I 989), 60, 592 598 Br J Cancer (1989), 60, 592-598 Risk factors for ovarian cancer: © a case -control The Macmillan Press Ltd., 1989 The Macmillan Press Ltd., study M Booth', V Beral3 & P Smith2 'Epidemiological Monitoring Unit and 2Tropical Epidemiology Unit, Department of Epidemiology & Population Sciences, London School of Hygiene and Tropical Medicine, Keppel Street (Gower Street), London WCIE 7HT, UK; and 31mperial Cancer Research Fund, Epidemiology & Clinical Trials Unit, Radcliffe Infirmary, Oxford OX2 6HE, UK Summary A hospital-based case-control study of ovarian cancer was conducted in London and Oxford between October 1978 and February 1983 Menstrual characteristics, reproductive and contraceptive history and history of exposure to various environmental factors were compared between 235 women with histologically diagnosed epithelial ovarian cancer and 451 controls High gravidity, hysterectomy, female sterilisation and oral contraceptive use were associated with a reduced risk of ovarian cancer Infertility and late age at menopause were associated with an increase in risk While these factors were related, they were each found to be independently associated with ovarian cancer risk after adjusting for the effect of the other factors While results from recent case -control studies have consistently shown that multiparity and oral contraceptive use are associated with a reduced risk of ovarian cancer, the association of the cancer with other reproductive, hormonal and related factors such as age at menopause, history of hysterectomy or use of oestrogen replacement therapy is less clear We have conducted a hospital-based case-control study in London and Oxford which was designed to investigate the independent contributions of reproductive history and contraceptive use to ovarian cancer risk In particular, it was planned to attempt to segregate out the effect on risk of infertility from that of voluntary limitation of family size The association between ovarian cancer and other possible aetiological agents was also examined Subjects and methods Between October 1978 and February 1983 five interviewers identified and questioned women with a diagnosis of ovarian cancer and women selected as controls at 13 hospitals in London and two in Oxford A standard questionnaire was used to obtain information on reproductive and menstrual history and on exposure to various substances such as exogenous oestrogens, cigarettes and talc A month by month record was made of the specific contraceptive methods used by each woman between the ages of 16 and 45 years, or, if under 45 years, up to the time of diagnosis (cases) or interview (controls) The methods were classified as sheaths, diaphragms, intrauterine devices, oral contraceptives or 'other methods' (spermicides, rhythm and coitus interruptus) Women who reported using a contraceptive diaphragm were asked if they had stored it in talc Also recorded were months during which a woman was not using contraception due to sexual abstinence, pregnancy, menopause or because she or her partner had been sterilised The other months when a woman reported using no method of contraception although sexually active have been classified as months of 'unprotected intercourse' The total duration of use of each contraceptive method, of any contraceptive method, of unprotected intercourse and of pregnancy were computed for each woman The study was confinied to women aged less than 65 years whose diagnosis of ovarian cancer had been made within two years of interview A total of 280 cases were interviewed and pathological specimens were histologically classified by Professor C Hudson and Dr M Curling from St Bartholomews Hospital A total of 235 women with epithelial ovarian cancer were included in the analyses For these women, the tumour type was described as serous in 101 (43%) cases, mucinous in 38 (15%) cases, endometrioid in 52 (22%) cases Correspondence: M Booth Received February 1989; and in revised form May 1989 and clear cell in 12 (5%) cases Mixed and undifferentiated types of epithelial tumours accounted for the remaining 32 (14%) cases Excluded from the analyses were nine women with a non-epithelial ovarian neoplasm, 11 with a primary tumour in an unknown site outside the ovary, 21 with a primary tumour in an unknown site although one consistent with an ovarian origin, one with a benign tumour and three for whom pathology material could not be obtained For each case it was planned to select two age-matched controls from women being treated in the same hospital Women with bilateral oophorectomy were excluded from the control group as were women admitted with conditions that have been related to reproductive history or oral contraceptive use (all circulatory and gynaecological diseases, gallbladder and thyroid diseases, rheumatoid arthritis, malignant disease of the breast, uterus and bladder, and melanoma) It proved logistically impossible to select two age-matched controls for each case from the same hospital and it was decided merely to ensure that the age distribution of the controls was approximately the same as that of the cases For 63 cases recruited from a London hospital where only cancer patients are treated, controls were selected from other London hospitals For these reasons, the data were analysed using an unmatched approach with adjustments being made to relative risk estimates for age and socio-economic status A total of 451 controls have been included in the analyses The admission diagnoses for these patients were gastrointestinal disease (105), bone or joint disease (70), respiratory disease (39), renal or other urinary disease (35), neurological disease (30), fractures or other injuries (28), skin or subcutaneous tissue disease (17), malignant neoplasms of the digestive organs (15) and bone or skin (2), benign neoplasms of the digestive organs (4) respiratory system (4) and other sites (8) and various other conditions and symptoms (94) This final category included patients with haemorrhoids (15) and those with symptoms relating to the respiratory system (10), gastrointestinal tract (20) and urinary system (10) Maximum likelihood estimates of relative risk (RR) together with their 95% confidence interval (95% CI) and tests for trend where appropriate were computed by multiple logistic regression techniques (Breslow & Day, 1980) using the GLIM statistical package (Baker & Nelder, 1978) All relative risks have been adjusted for age in 5-year strata (20-24, 25-29, 60-64) and for social class in six categories (1,II,JII non-manual, III manual, IV and V) Age of the cases was taken as age at diagnosis of ovarian cancer and of the controls as age at interview Social class was based on occupation (Office of Population Censuses and Surveys, 1970) using husband's occupation for ever married women and own occupation for those who had never married Other relative risk adjustments and tests for trend have been made with the exposures as continuous variables When the data were examined by place of interview (London or Oxford), there were no notable differences in the risk estimates RISK FACTORS FOR OVARIAN CANCER associated with the major variables of interest The relative risks have not, therefore, been stratified by place of interview The terms nulligravid and gravid have been used to denote, respectively, women who have never knowingly conceived and women who have had at least one pregnancy Parity has been defined as number of live and still births Results The age distributions of the cases and controls are shown in Table I The average age of the cases was slightly higher than that of the controls There was an excess of cases in social classes I, II, and III non-manual (58%) as compared to controls (43%) (P = 0.05) and, because of this, all relative risks have been adjusted for social class as well as age Table II shows the relative risks for ovarian cancer associated with various aspects of pregnancy history Nulligravid women had a higher risk of ovarian cancer than gravid women (RR = 1.7, 95% CI 1.1-2.6) The relative risks were elevated both in nulligravid women who had been sexually active and in those who had not, although significantly so only for the sexually active Among those who had ever been pregnant, the relative risks decreased as the number of pregnancies increased, (X2 (trend) = 4.3, P 10 Age at first OC (years) Never used 0.4 0.3 0.4 0.5 RR 0~~ use 306 178 19 24 12 25 46 ,2for trend within users 1.0" = 0.5 0.8 0.8 0.3 2.6 (0.2 1.5) (0.4- 1.9) (0.3 - 1.9) (0.1 -0.7) Age (years) 14 12- 13 < 12 197 97 185 89 66 46 X2 for trend = 0.03 l.Oa 0.9 1.3 595 (0.6- 1.3) (0.8-2.1) Age at natural menopause (years)c < 45 45-49 1.oa 34 10 2.0 (0.9-4.7) 77 47 2.5 (1.1-5.8) 84 99 >50 X2 for trend =7.1 P 40 1.0a 2.0 2.0 4.3 X2 for trend = 17.8 P < 0.001 1.0 2.4 2.4 5.0 X2 for trend = 12.3 P